The Neurobiology of Sleep
and Sleep Disorders
Tamara Blutstein, Ph.D.
Department of Neuroscience
Tufts University School of Medicine
May 1, 2013
What is Sleep?
“a natural periodic state of rest for the mind
and body, in which the eyes usually close and
consciousness is completely or partially lost
so that there is a decrease in bodily
movement and responsiveness to external
stimuli”
The Function of Sleep
• Important to overall health and well being
– Severe cognitive and physical consequences of sleep deprivation
– Strong rebound of sleep following sleep loss
– Evolutionarily conserved
• There are a number of sleep disorders
– Insomnia, sleep apnea, restless leg syndrome, narcolepsy
• Sleep disruptions are associated with a number of
neurological disorders
– Parkinson’s disease, Alzheimer’s disease, depression
Two Process Model of Sleep
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Balance between sleep and wake determined by 2 factors
– Circadian
• 24hr cyclic rhythm generated by the SCN that entrains the sleep-wake cycle to the daily
light-dark cycle
– Homeostatic
• Determined by sleep need
• Homeostatic drive to sleep increases with time awake and peaks just before the
beginning of the sleep period
Lu and Zee 2010
Sleep Stages
Wake- desynchronized EEG and high
EMG activity
WAKE
EMG
EEG
NREM sleep- high amplitude, slowwave EEG (delta frequency 0.54Hz) and low EMG activity relative
to wakefulness
NREM
EMG
EEG
REM
REM sleep- regular theta activity (48Hz) on EEG, coupled with low
EMG activity relative to that of
NREM sleep
EMG
EEG
Human Sleep
WAKE
NREM Sleep
Divided into 4 stages
Stage 1
2-5% of TST
Transition from wake to sleep
Stage 2
45-55% of TST
Increased slow waves, presence of sleep
spindles and K complexes
Stage 3 and 4
10-20% of TST
Slow-wave sleep (SWS), greatest early in
sleep period
REM Sleep
20-25% TST
Episodes longer as sleep progresses
Stiller and Postolache 2005
Neurobiology of Sleep:
Wake-Promoting Systems
Espana and Scammell 2011
Neurobiology of Sleep:
NREM
Espana and Scammell 2011
Regulation fo Wake and Sleep:
Flip-Flop Switch
Lu and Zee 2010
Neurobiology of Sleep:
REM
Espana and Scammell 2011
Neurotransmitters Involved in
Sleep/Wake
Espana and Scammell 2011
International Classification of Sleep
Disorders
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Insomnias
Sleep-related breathing disorders
Hypersomnias of central origin
Circadian rhythm sleep disorders
Parasomnias
Sleep-related movement disorders
Isolated symptoms (apparently normal
variants and unresolved issues)
• Other sleep disorders
Insomnias
• Most common
• Difficulty initiating and maintaining sleep,
early morning awakening, non-restorative
sleep
• Occurs 3-4 times per week and persisting
for more than a month
• Sleep difficulty occurs despite adequate
opportunity and circumstances for sleep
and associated with daytime dysfunction
Primary Insomnias
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Adjustment insomnia
Psychophysiological insomnia
Paradoxical insomnia
Idiopathic insomnia
Inadequate sleep hygiene
Behavioral insomnia of childhood
Secondary Insomnias
• Insomnia due to a drug or substance
• Insomnia due to a medical condition
• Insomnia not due to a substance or known
physiological condition
• Physiologic Insomnia, unspecified
Causes of Insomnia
• Hyperactivity of HPA axis
• Imbalance of flip-flop switch regulating
transition from sleep to wake
Treatment for Insomnias:
Cognitive-Behavioral
Buysse 2013
Treatment for Insomnias:
Pharmacology
Buysse 2013
Treatment for Insomnias:
Pharmacology
Buysse 2013
Sleep-Related Breathing Disorders
• Characteristic feature: disordered
ventilation during sleep
• Primary central sleep apnea
• Primary sleep apnea of infancy
• Sleep-related hypoventilation/hypoxemic
syndromes
• Obstructive sleep apnea
Obstructive Sleep Apnea
CPAP
Ioachimescu and Collop 2012
Hypersomnia of Central Origin
• Primary complaint is daytime sleepiness
and the cause is not disturbed nocturnal
sleep or misaligned circadian rhythms
• Daytime sleepiness: inability to stay alert
and awake during the major waking
episodes of the day, resulting in
unintended lapses into sleep
Hypersomnia of Central Origin
• Recurrent hypersomnia
• Idiopathic hypersomina with or without
long sleep time
• Hypersomnia due to a medical condition
• Narcolepsy-cataplexy syndrome
Narcolepsy-Cataplexy Syndrome
• Onset in adolescents and young adults
• Narcolepsy with cataplexy, without, and
secondary narcolepsy
• Irresistible desire to fall asleep in
inappropriate circumstances
• Triggered by emotional factors such as
laughter, rage or anger
Narcolepsy-Cataplexy Syndrome
• Video
Narcolepsy-Cataplexy Syndrome
Burgess and Scammell 2012
Circadian Rhythm Sleep Disorders
• Delayed sleep phase
• Advanced Sleep
Phase
• Jet lag
• Shift work
Drake 2010
Circadian Rhythm Sleep Disorders
• Changes in the period length of the
circadian clock
• Impaired response to light
• Altered function of clock genes or products
• Behavior therapy, Light therapy and
Chronotherapy
Parasomnias
Tinuper et al 2012
Parasomnias
• NREM parasomnias, impaired arousal
mechanisms and the persistence of sleep
drive result in a failure of the brain to fully
transition into wake
• REM parasomnias-failure of mechanisms
that induce muscle atonia
• Most treatments are similar to those used
for insomnia
• Safety measures
Sleep-Related Movement Disorders
• Characterized by relatively simple,
stereotyped movements that disturb sleep
• Bruxism
• Rhythmic movement disorder
• Nocturnal leg cramps
• Restless leg syndrome
Isolated Symptoms, Apparently Normal
Variants and Unresolved Issues
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Long sleepers
Short sleepers
Snoring
Sleep talkers
Sleep related sexual disorders
Drug Effects on Sleep
Espana and Scammell 2011
Consequences of Sleep Loss
Wulff et al 2010
Consequences of Sleep Loss
Wulff et al 2010
Consequences of Sleep Loss
Wulff et al 2010
Neurological Disorders and Sleep
Wulff et al 2010
Sleep in Psychiatric Disease
Wulff et al 2010
Sleep in Psychiatric Disease
Wulff et al 2010
Sleep in Psychiatric Disease
Wulff et al 2010
Sleep in Neurodegenerative Disease
Wulff et al 2010
Neurological Disorders and Sleep
• Therapeutic target
• Mechanistic overlap
• Identification of risk
factors and vulnerability
Questions?
Contact info
Email: Tamara.Blutstein@tufts.edu